The compound CI-979 is a newly discovered cognition activator as described in U.S. Pat. No. 4,786,648 which disclosure is herein included by reference in the present specification. The compound CI-979 has been discovered as having pharmacological properties that make them useful as cognition activators. Therefore, the compound has been under consideration for therapy of age-associated memory impairment and primary degenerative dementia. Furthermore, CI-979 HCl is being developed for the treatment of Alzheimer's disease.
Specifically, CI-979, has the following structural formula (A): ##STR1##
As can be seen in formula (A), CI-979 contains a methyloxime group attached to a basic tetrahydropyridine ring (1,2,5,6-tetrahydro-l-methyl-3-pyridine methyloxime). Similar to other pyridine derivatives, the free base form of CI-979 is a volatile liquid, whereas CI-979 hydrochloride is a stable white crystalline salt.
In the course of preformulation testing, the storage stability of the drug and aqueous solutions of CI-979 HCl has been studied by exposure to heat, UV light, and the pH range (see FIG. 1). Specifically, it has been found that the HCl salt will convert in the presence of basic or neutral solid excipients to a free base form in the air and consequently evaporate. Furthermore, in acidic environments of less than pH5 the drug undergoes hydrolysis to an aldehyde degradation product. Acid labile compounds such as CI-979 thus require a special formulation in order to serve effectively as a pharmaceutical oral dosage. The acid hydrolyzed products of the drug CI-979 HCl are virtually devoid of any biological activity.
For the purpose of overcoming acid lability of the drug, one skilled in the art is acquainted with a number of acid protective formulations.
U.S. Pat. No. 5,045,321 discloses a stabilized pharmaceutical preparation (col. 14, Ex 8) wherein nonpareils are dust-coated using an aqueous hydroxypropylcellulose spray as binder, followed by an enteric coating.
U.S. Pat. No. 4,882,169 describes coated pellets having a core comprising at least one active ingredient, optionally, one or more intermediate layers, and a swellable outer layer. The core is defined as containing optional excipients as, e.g., binders, plasticers, glidants, absorbing substances and/or swellable materials.
U.S. Pat. No. 4,853,230 discloses pharmaceutical oral formulations of acid-labile substances. In particular, a pharmaceutical dosage form is formulated to prevent substances from coming in contact with gastric juice. An alkaline core is thus coated with enteric coating, e.g., with cellulose acetate phthalate, permitting dissolution and absorption within the proximal portion of the small intestine.
European Patent Application No. 0377518 A2 for sustained release pharmaceutical composition of a spheroidal core element composed of at least one active ingredient, and core coatings soluble to varying degrees at different pH ranges directed to a therapeutic effect over an extended period of time.
However, these methods are deficient in providing stability to dry triturates of a drug such as CI-979 HCl which is both rapidly degraded under acidic conditions and lost by evaporation under neutral or alkaline conditions due to conversion to the volatile free base.